1. Field of the Invention
The invention relates to a novel and facile process for making arylmaleic acid and arylmaleic anhydride derivatives, which are used as intermediates in the preparation of aryl-maleimides. The arylmaleimides are subsequently used to synthesize compounds which possess activity as antidepressants and as antistress agents in mammals.
2. Description of the Related Art
The Meerwein arylation of maleimides (Rondestvedt, C. S. Jr.; Vogl, O. J. Amer. Chem. Soc., 1955, 77, 2313) or dialkylmaleates (Taylor, G. C., Strojny, E. J., J. Amer. Chem. Soc., 1954, 76, 1872) is the most general method of making arylmaleic acid derivatives. Several factors preclude scaleup of the above reactions. In particular, the maleimides used are expensive and the arylations are always accompanied by a substantial quantity of aryl coupling to form biphenyls.
Another method explored involves a Wittig reaction of aroyl cyanides with carbalkoxymethylenetriphenylphosphoranes (Kalvode, L. Coll. Czech. Chem. Comm., 1976, 41 2034). In our hands, the reaction of commercially available benzoyl cyanide with carboethyoxymethylenetriphenylphosphorane gives ethyl 3-cyano-3 -phenylpropenoate as a 2.5:1 mixture of Z:E isomers.
This ratio can be improved to about 10:1 Z:E by treatment of the mixture with thiophenol in refluxing toluene. The desired Z-cyanoester is then crystallized in hot formic acid to phenylmaleimide. Despite the overall efficiency, this method is impractical due to the lack of availability of the desired aroyl cyanides.
The prior art references are directed to laboratory scale synthesis. Attempts to produce the arylmaleic acid derivatives in a large scale according to the prior art procedures have proven to be unsatisfactory as detailed above.
This novel and facile process gives the arylmaleic acid derivatives in high yield. In addition, a highly pure product, a single geometric isomer, is obtained without the need for further purification, such as chromatography of the Z:E isomeric mixture.